Suppression of TGF-β1/SMAD pathway and extracellular matrix production in primary keloid fibroblasts by curcuminoids: its potential therapeutic use in the chemoprevention of keloid

Abstract

Keloid is a fibrotic disease characterized by abnormal accumulation of extracellular matrix (ECM) in the dermis. It is a late spreading skin overgrowth and may be considered a plastic surgeon's nightmare. In nature, curcuminoid is composed of curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (bDMC). Curcuminoids have been found to inhibit fibrosis. However, their role in the synthesis of ECM in the keloid fibroblasts (KFs) has remained unclear. In this series of studies, a total of seven primary KFs cultures were used as the KFs model for investigating the inhibitory effect of curcuminoids on the expression of ECM and TGF-β1. A sensitive and reproducible HPLC method was developed to provide a quantitative analysis on the cellular uptake of curcuminoids onto the KF cells. The level of ECM in the primary KFs was elevated. The elevation of ECM and TGF-β1/p-SMAD-2 level was substantially blocked by the cellular uptake of curcumin in a dose-dependent manner in all the seven primary KFs. The results have led to the conclusion that the excessive production of ECM in the KF cells could be blocked and/or rapidly decreased by curcumin.

Downregulation of type I collagen expression in silibinin-treated human skin fibroblasts by blocking the activation of Smad2/3-dependent signaling pathways: Potential therapeutic use in the chemoprevention of keloids

“…It has been widely accepted that the dysregulation of the TGF-β/Smad pathway plays a key role in hypertrophic or keloid scar formation in human skin tissues. A number of studies have clearly demonstrated that the increased expression of TGF-β receptors (types I and II) and the increased phosphorylation of Smad3 in keloid fibroblasts compared to normal HSFs, as well as the suppression of the TGF-β1/Smad pathway by certain chemicals such as curcumin, may exert chemopreventive effects, thus preventing keloid formation (7)(8)(9).…”

“…Receptor-activated Smads (R-Smads; Smad2 and Smad3) are the key intracellular components in the TGF-β1 signaling pathway involved in the production of type I collagen. Thus, the dysregulation of the TGF-β1/Smad pathway is crucial for the pathogenesis of hypertrophic and keloid scar formation (7,8).…”

Role of TGF-β signaling in curcumin-mediated inhibition of tumorigenicity of human lung cancer cells

“…Although little is known about the effect of curcumin on TGF-β signaling in fibroblast cells (Gaedeke et al 2004; Hsu et al 2010), nothing is known about the role of curcumin on TGF-β signaling in lung cancer cells. In our previous experiments, we have observed that TGF-β signaling has no role in curcumin-induced growth inhibition, apoptosis (Fig.…”

“…Several growth factors and exogenous small molecule inhibitors function as tumor suppressors or promoters through cross-talking with the TGF-β signaling pathway. Curcumin, as a tumor suppressor, was reported to regulate TGF-β signaling cascade in neonatal lung fibroblast (Sakurai et al 2011), renal cells (Gaedeke et al 2004), keloid fibroblasts (Hsu et al 2010), and scleroderma fibroblasts (Song et al 2011). However, to our knowledge, nothing is known about the effect of curcumin on TGF-β signaling in lung cancer cells of epithelial origin and whether TGF-β-induced tumor suppressor function is involved in curcumin-mediated antitumor activities.…”

Aspidin PB, a novel natural anti-fibrotic compound, inhibited fibrogenesis in TGF-β1-stimulated keloid fibroblasts via PI-3K/Akt and Smad signaling pathways

“…Recently, active components of medicinal plant extracts have been reported to be effective in treatment keloid fibroblast, as well as inhibiting implanted nodule development and collagen synthesis, implying a potential therapeutic option for treatment of keloids [29][30][31]. Aspidin PB, isolated from D. fragrans (L) Schott, is also a phloroglucinol derivative.…”